Interaksi antara Polimorfisme Genetik Metilentetrahidrofolat Reduktase dan Metabolisme Folat pada Hipertensi Esensial

SUNARTI, Promotor Prof.dr. Abdul Salam M. Sofro, Sp.KT.,Ph.D

2007 | Disertasi | S3 Ilmu Kedokteran

Hipertensi esensial berhubungan dengan gangguan vasodilatasi tergantung endotel akibat penurunan ketersediaan nitrit oksid (NO). Penurunan NO dapat disebabkan oleh hiperhomosisteinemia akibat mutasi C677T MTHFR dan defisiensi folat. Tujuan penelitian ini untuk mengidentifikasi pengaruh mutasi C677T MTHFR dan atau defisiensi folat terhadap kadar homosistein dan risiko hipertensi. Penelitian kasuskontrol ini tersarang pada penelitian Survaillance of Non-Communicable Diseases di Kabupaten Purworejo Jawa Tengah. Subyek kasus penelitian adalah laki-laki hipertensi esensial, umur 20-60 tahun, mempunyai kadar kreatinin urin, glukosa, kolesterol, trigliserida darah normal, tidak minum obat antihipertensi atau antihiperhomosisteinemia. Subyek kontrol diambil dari penduduk yang sama dengan subyek kasus tetapi tidak hipertensi. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism digunakan dalam analisis mutasi C677T MTHFR. Kadar folat darah ditentukan dengan time resolved-fluorometry. High Pressure Liquid Chromatography digunakan untuk mengukur kadar total homosistein plasma. Kadar NO ditetapkan dengan spektrofotometri. Distribusi frekuensi genotip CC, CT, TT dari mutasi C677T MTHFR pada hipertensi esensial adalah 75%, 25% dan 0%; sedangkan frekuensi alel C adalah 0,875 dan alel T adalah 0,125. Pada kontrol, distribusi frekuensi genotip CC, CT, TT adalah 81%, 19% dan 0%, sedangkan frekuensi alel C adalah 0,905 dan alel T adalah 0,095. Odds ratio untuk mengalami hipertensi subyek yang membawa genotip CT adalah 1,36 (CI: 95%:0,50;3,70) dan subyek dengan defisiensi folat adalah 1,40 (CI: 95%:0,57;3,45). Bila subyek membawa genotip CT dan mengalami defisiensi folat maka odds ratio untuk mengalami hipertensi adalah 2,30 (CI: 95%:0,45;15,00). Kadar homosistein pada kelompok kasus dengan defisiensi folat dan genotip CT yaitu 45.28 + 30.39 μmol/L, defisiensi folat saja yaitu 17.94 + 12.77 μmol/L dan genotip CT saja yaitu 13,04 + 4,69 μmol/L. Kadar homosistein pada kontrol dengan defisiensi folat dan genotip CT yaitu 21,44 + 10,71 μmol/L, hanya defisiensi folat yaitu 11,79 + 5,28 μmol/L dan genotip CT saja yaitu 11,54 + 4,23 μmol/L. Pada semua subyek kasus dan kontrol yang tidak defisiensi folat, kadar homosisteinnya tidak dipengaruhi oleh genotip CT. Kadar folat berkorelasi negatif dengan kadar homosistein (p=0,001) dan kadar homosistein berkorelasi negatif dengan kadar NO (p=0,016). Pada subyek umur 20-39 tahun, hubungan antara kadar NO dan kejadiaan hipertensi tidak berbeda signifikan (OR=0,754; p=0,062), sedangkan pada subyek umur 40-60 tahun hubungan tersebut berbeda signifikan (P=0,005; OR=0,764). Dengan ini dapat disimpulkan bahwa frekuensi alel T dari mutasi C677T gen MTHFR pada laki-laki di populasi Jawa adalah rendah. Pengaruh defisiensi folat terhadap kadar homosistein dan risiko hipertensi lebih kuat sedikit dibandingkan efek genotip CT dari mutasi C677T gen MTHFR. Kadar folat darah merupakan penentu utama kadar homosistein subyek hipertensi yang membawa genotip CT. Genotip CT tidak mempengaruhi kadar homosistein. Pengaruh kadar NO terhadap risiko hipertensi hanya signifikan pada subyek umur 40-60 tahun. Efek NO terhadap tekanan darah lebih tinggi pada tekanan sistolik dibandingkan diastolik.

Essential hypertension is related with endothelium-dependent vasodilatation disorder that results from decrease of nitric oxide (NO) bioavailability. Decrease of NO bioavailability can be caused by hyperhomocysteinemia that result from MTHFR C677T mutation and folate deficiency. The aims of this research were to identify the effect of MTHFR C677T mutation and or folate deficiency on homocysteine level and hypertension risk. This was a nested case control in surveillance of non-communicable diseases study in District of Purworejo, Central Java. The cases of the study were male with essential hypertension of 20-60 years old having normal level of urine creatinine, blood glucose, cholesterol and triacyglyceride, did not take any antihypertension or antihyperhomocysteinemia drugs. The controls were individuals having the same criteria with the cases but they did not have hypertension. PCR-RFLP was used to analyze MTHFR C677T mutation. The blood folate level was determined by time resolved-fluorometry. High Pressure Liquid Chromatography was used to identify total plasma homocysteine level. Nitric oxide level was determined using spectrophotometry. The frequency distribution of CC, CT, TT genotypes of MTHFR C677T mutation in essential hypertension was 75%, 25% and 0% respectively; whereas frequency of C allele was 0,875 and T allele was 0,125. In the control, the frequency distribution of CC, CT and TT was 81%, 19% and 0%, respectively; whereas frequency of C allele was 0,905 and T was 0,095. Odds ratio to have hypertension in subjects carry CT genotype was 1.36 (CI: 95%:0.50; 3.70), subjects with folate deficiency was 1.40 (CI: 95%:0.57; 3.45), and subjects with both carry CT genotype and folate deficiency was 2.30 (CI: 95%:0.45;15.00). Homocysteine level in the cases with both folate deficiency and CT genotype was 45.28 + 30.39 μmol/L, only folate deficiency was 17.94 + 12.77 μmol/L, and only CT genotype was 13,04 + 4,69 μmol/L. Homocysteine level in the control with both folate deficiency and CT genotype was 21.44 + 10.71 μmol/L, only folate deficiency was 11.79 + 5.28 μmol/L, and only CT genotype was 11,54 + 4,23 μmol/L. In all subjects without folate deficiency, the homocysteine level was not influenced by the CT genotype. The plasma folate level was negatively correlated with homocysteine (p=0,01), and the plasma homocysteine level was negatively correlated with nitric oxide level (p=0,016). The systolic and diastolic blood pressure of the subjects of 40-60 years old were significantly influenced by plasma NO level (psyst.=0,005; pdiast=0,045), but not in the subjects of 20-39 years old (psyst.=0,106; pdiast=0,269). In the subjects of 20-39 years old, the correlation between blood nitric oxide level and hypertension risk was not (OR=0.754; p=0.062) significantly different, whereas in the subjects of 40-60 years old, it was (OR=0.764; p=0.005) significantly different. allele of MTHFR C677T mutation was low. The effect of folate deficiency upon homocysteine level and hypertension risk was slightly higher than the effect of CT genotype of MTHFR C677T mutation. Blood folate level was major determinant of blood homocysteine level in hypertensive individuals carry CC genotype. The CT genotype did not influence homocysteine level. The effect of NO level upon hypertension risk was only significant in the subjects of 40-60 years. The effect of NO on blood pressure was higher in systolic than diastolic pressure.

Kata Kunci : Hipertensi Esensial,Folat,MTHFR,Nitrit Oksid,Homosistein, hypertension, folate, MTHFR, homosysteine, nitric oxide